This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Virus-specific CD8+ T cells often avoid causing severe immunopathology by strictly regulating their cytokine production and turning cytokine secretion on, off, and on again in response to direct antigen contact. In contrast, interleukin-12 (IL-12) and interleukin-18 (IL-18) represent two potent inflammatory cytokines that trigger interferon-gamma (IFNg) production by activated T cells in the absence of direct antigen contact. Although activated CD8+ T cells are known to respond to IL-12/IL-18 stimulation, the effects of these cytokines on long-term, resting memory T cells is largely unknown and represents a significant gap in our understanding of this phenomenon. In our proposed studies, we will compare and contrast effector and memory T cells of a defined specificity in terms of: 1) cytokine production, 2) cytolytic activity, 3) proliferation, and 4) global gene expression following stimulation with IL-12 and IL-18. This information will be important for understanding how IL-12/IL-18 secretion might be used by infected cells as an intrinsic "danger" signal to trigger antimicrobial immune responses by nearby antigen-experienced T cells without requiring direct TcR stimulation. On the other hand, this loss of antigen specificity also appears to play a substantial role in certain types of T cell-mediated immunopathology associated with secondary bacterial infections and septic shock. For these reasons, a thorough understanding of cytokine-mediated T cell activation is critical for learning how to maintain or augment appropriate T cell responses while at the same time decreasing T cell-associated symptoms of disease.